Cleaning validation citations on 483s, warning letters rising: 40% of API audit 483s had items on cleaning.Dear Reader,
A pharmaceutical industry consultant, who conducts GMP GMP (guanosine monophosphate): see guanine. audits and evaluations of chemistry, manufacturing and controls (CMC (Common Messaging Calls) A programming interface specified by the XAPIA as the standard messaging API for X.400 and other messaging systems. CMC is intended to provide a common API for applications that want to become mail enabled.
1. ), said last month that many of the 483s and warning letters she reviews cite insufficient or lack of cleaning validation The introduction to this article provides insufficient context for those unfamiliar with the subject matter.
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Barbara Unger, consultant with Don Hill & Associates of Silver Spring, MD, urged participants at an International Business Communications conference in San Diego San Diego (săn dēā`gō), city (1990 pop. 1,110,549), seat of San Diego co., S Calif., on San Diego Bay; inc. 1850. San Diego includes the unincorporated communities of La Jolla and Spring Valley. Coronado is across the bay. to beef up their cleaning protocols and validation to meet regulatory expectations.
Unger, a former Eli Lilly Eli Lilly can refer to:
Food and Drug Administration
n.pr See Food and Drug Administration.
n.pr the abbreviation for the Food and Drug Administration. . In
483 observations and recent warning letters that I've reviewed, in about 40% of those given to API (Application Programming Interface) A language and message format used by an application program to communicate with the operating system or some other control program such as a database management system (DBMS) or communications protocol. manufacturers there has been at least one item dealing with cleaning." Common deficiencies Unger noted include:
1. Process tanks are routinely reused before cleaning, and no cleaning validation data are available to support this practice.
2. No data exist to support the manual cleaning of centrifuge centrifuge (sĕn`trəfyj), device using centrifugal force to separate two or more substances of different density, e.g., two liquids or a liquid and a solid. bowls.
3. Approved cleaning procedures are not specific and are not validatable.
4. Inadequate cleaning of lyophilizer, in that worst-case sampling locations are not identified, and sampling techniques have not been validated.
5. Inadequate production tank cleaning procedures exist. Specifically, validated hold times are not included in the cleaning procedure; cleaning SOPs lack sufficient detail; and no verification of visual inspection for cleanliness Cleanliness
See also Orderliness.
Cleverness (See CUNNING.)
unkempt herself, demands cleanliness from others, especially children. [Ger. Folklore: Leach, 137]
continually “washes” itself. .
Unger outlined four areas that regulators expect developers and manufactures to address adequately in their application cleaning plans.
First, the cleaning methodology must be consistent and justified for each piece and type of equipment. It is often best to classify families of equipment, based on criteria such as product contact, equipment construction, internal complexity, length or complexity of piping runs, or the nature of residues. Firms may "make a business case to dedicate certain equipment to certain families of products," Unger said.
She said cleaning protocols must identify what the cleaning process is intended to remove, and how. This includes evaluating the chemical and physical properties of the soils, particularly solubility solubility
Degree to which a substance dissolves in a solvent to make a solution (usually expressed as grams of solute per litre of solvent). Solubility of one fluid (liquid or gas) in another may be complete (totally miscible; e.g. . Cleaning agents and their concentrations must be identified, as must the temperatures and volumes of rinses and cleaning solutions.
Unger said sampling methods must be specified and validated, including visual examination of cleanliness, rinse solution testing and taking surface swabs.
"The definition of 'clean' must include a definition of 'visually clean,'" she added. Unger also said a manufacturer's plan must also define what a soiled surface looks like. When calculating carryover, cleanliness calculations must cover pediatric pediatric /pe·di·at·ric/ (pe?de-at´rik) pertaining to the health of children.
Of or relating to pediatrics. (10 kg) dosing, and not just adult (70 kg) dosing. "For multi-product facilities, all soils should be sampled under identical conditions," she added.
Second, facilities must document how critical cleanliness parameters will be controlled. Hard-to-clean areas, such as dip tubes and baffles, must be identified in the equipment and piping designs.
"Don't forget or ignore automation," Unger warned. Automation provides a source of variability, and instrumentation packages running CIP (1) (Common Isochronous Packet) The packet format used in time-based (real time) FireWire transmission. See FireWire, IEC 61883 and mLAN.
(2) (Common Industrial P must be evaluated. "Software can say one thing and the equipment can behave in a different manner," she said.
In addition, Unger advised industry to account for cycle times when planning manufacturing capacity and scheduling. "Leave time for adequate cleaning!" she urged.
Unger added that manual operations, which are often hard to control, must specify how cleanliness standards will be maintained, especially among multiple operators.
Third, cleaning protocols must establish and justify "worst case" conditions. "These should include considerations of the equipment and piping configurations, allowable time limits before and after use, and a hierarchy of the relative cleanability of soils," Unger advised.
Finally, Unger reminded the audience that regulators expect that acceptance criteria for cleanliness are practical, achievable and justified. "It's not just a box-checking exercise."
Sincerely, The Editors